Studies with purified mast cells from rat tissues have shown that in the presence of physiological concentrations of histidine the rate of histamine synthesis is much greater in the intact cell than that in extracts of these cells and that histidine uptake is an essential component of the histamine synthetic pathway in the intact cell. Histamine synthesis is suppressed by inhibitors both of histidine transport and histidine decarboxylase. In many species histamine-N-methyltransferase is a key enzyme in the inactivation of histamine. We suggested that the enzyme possesses an inhibitory site with an affinity for histamine and a variety of H2 histamine receptor agonists and on this basis looked for new inhibitors of the enzyme. One compound, SKF 91488 was found to be a particularly strong noncompetitive inhibitor (Ki 9- x 10 to the minus 7th power M of the enzyme in vitro and in vivo.